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Structural differences determine the relative selectivity of nicotinic compounds for native α4β2^*-, α6β2^*-, α3β4^*- and α7-nicotine acetylcholine receptors

Grady, Sharon R. and Drenan, Ryan M. and Breining, Scott R. and Yohannes, Daniel and Wageman, Charles R. and Fedorov, Nikolai B. and McKinney, Sheri and Whiteaker, Paul and Bencherif, Merouane and Lester, Henry A. and Marks, Michael J. (2010) Structural differences determine the relative selectivity of nicotinic compounds for native α4β2^*-, α6β2^*-, α3β4^*- and α7-nicotine acetylcholine receptors. Neuropharmacology, 58 (7). pp. 1054-1066. ISSN 0028-3908. PMCID PMC2849849.

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Mammalian brain expresses multiple nicotinic acetylcholine receptor (nAChR) subtypes that differ in subunit composition, sites of expression and pharmacological and functional properties. Among known subtypes of receptors, α4β2^* and α6β2^*-nAChR have the highest affinity for nicotine (where ^* indicates possibility of other subunits). The α4β2^*-nAChRs are widely distributed, while α6β2^*-nAChR are restricted to a few regions. Both subtypes modulate release of dopamine from the dopaminergic neurons of the mesoaccumbens pathway thought to be essential for reward and addiction. α4β2^*-nAChR also modulate GABA release in these areas. Identification of selective compounds would facilitate study of nAChR subtypes. An improved understanding of the role of nAChR subtypes may help in developing more effective smoking cessation aids with fewer side effects than current therapeutics.We have screened a series of nicotinic compounds that vary in the distance between the pyridine and the cationic center, in steric bulk, and in flexibility of the molecule. These compoundswere screened usingmembrane binding and synaptosomal function assays, or recordings from GH4C1 cells expressing hα7, to determine affinity, potency and efficacy at four subtypes of nAChRs found in brain, α4β2^*, α6β2^*, α7 and α3β4^*. In addition, physiological assays in gain-of-function mutant mice were used to assess in vivo activity at α4b2^* and α6β2^*-nAChRs. This approach has identified several compounds with agonist or partial agonist activity that display improved selectivity for α6β2^*-nAChR.

Item Type:Article
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URLURL TypeDescription DOIArticle CentralArticle
Drenan, Ryan M.0000-0002-8141-8577
Lester, Henry A.0000-0002-5470-5255
Additional Information:© 2010 Elsevier Ltd. Received 2 July 2009. Received 2 July 2009; revised 18 January 2010; accepted 21 January 2010. Available online 28 January 2010. Portions of this work were presented as an abstract at the Society for Nicotine and Tobacco Research annual meeting 2008, rapid response poster: Synaptosomal assays as methods for identifying alpha6beta2*- nAChR selective compounds by SR Grady, C Wageman, I Fernandez, P Whiteaker, D Yohannes, M Bencherif, HA Lester, MJ Marks. The authors thank Allan C. Collins for many helpful discussions. Supported by National Cooperative Drug Discovery Group U19 DA019375 from the National Institutes of Health to HAL, MJM and MB. The Institute for Behavioral Genetics animal colony is supported by NIH grant DA015663 to Allan C. Collins and MJM. Three of the authors (SRB, DY, MB) are employees of Targacept, Inc., which holds patents on several of the compounds studied in this paper. All studies conducted at Targacept, Inc., and reported here were supported by DA019375.
Funding AgencyGrant Number
NIHU19 DA019375
Subject Keywords:TC2429; TC2403; TC1698; TC2242; TC6951; Varenicline
Issue or Number:7
PubMed Central ID:PMC2849849
Record Number:CaltechAUTHORS:20100604-114525877
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Official Citation:Structural differences determine the relative selectivity of nicotinic compounds for native α4β2*-, α6β2*-, α3β4*- and α7-nicotine acetylcholine receptors Pages 1054-1066 Sharon R. Grady, Ryan M. Drenan, Scott R. Breining, Daniel Yohannes, Charles R. Wageman, Nikolai B. Fedorov, Sheri McKinney, Paul Whiteaker, Merouane Bencherif, Henry A. Lester, Michael J. Marks
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:18567
Deposited By: Ruth Sustaita
Deposited On:04 Jun 2010 21:23
Last Modified:09 Mar 2020 13:18

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